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E ven in this era of targeted molecular therapies, an old drug can sometimes provide a surprising new benefit. A case in point, the diabetes drug metformin is emerging as a potential treatment for breast cancer on the basis of evidence that cancer patients with lower insulin levels have better outcomes. But using a diabetes drug to lower insulin levels in patients who are not diabetic has caused concern among some researchers, who say that doctors first need to know more about how metformin works in the oncology setting. First isolated as an active ingredient in the medieval herbal remedy goat’s rue, metformin has been used to treat type II diabetes for more than 50 years. The U.S. Food and Drug Administration ap proved its use in the United States in 1995, and it is now the most prescribed drug for type II diabetes, the adult-onset form of the disease that accounts for 90% – 95% of all diabetes cases. After several epidemiological studies linked metformin use to lower cancer rates and reduced risk of cancer death, some physicians proposed adding metformin to cancer treatment regimens. Among the fi rst to advocate its use was Pamela Goodwin , M.D., a medical oncologist at Mount Sinai Hospital in Toronto. In a recent editorial in the Journal of Clinical Oncology , Goodwin laid out a rationale for adding metformin to adjuvant breast cancer treatment, citing evidence that elevated insulin levels, often associated with obesity, may be a biological link connecting obesity with lower survival. “If you look at the effect of insulin, the women in the highest quartile of insulin levels in the studies that have been done all yield the same result: They have a triple risk of death,” Goodwin said. “If we could lower those insulin levels by 25%, we might see a 5% – 6% absolute improvement in outcome, and that’s huge.” Goodwin bases her optimism on several published studies, including a prospective cohort study of 512 nondiabetic women with early-stage breast cancer that she published in 2002. The study showed that women with the highest fasting insulin levels had three times the risk of recurrence and death compared with women with the lowest insulin levels. Other large studies have replicated this fi nding. The NCIsponsored Health, Eating, Activity, and Lifestyle (HEAL) study confi rmed that higher body mass index and lower physical activity levels are associated with higher insulin levels in breast cancer survivors and that women with invasive disease and the highest insulin levels have three times the risk of death of women with the lowest insulin levels. Melinda Irwin, Ph.D., an epidemiologist at the Yale School of Public Health in New Haven, Conn., presented those data at the American Association for Cancer Research’s prevention meeting last year. “The high-insulin effect is large,” said Michael Pollak , M.D., professor of oncology at McGill University in Montreal. “The adverse effect of high insulin on outcome of postmenopausal breast cancer is in the same order of magnitude as the benefi cial effect of adjuvant chemotherapy. This is nothing subtle.” Pollak, who studies the association of high insulin levels with breast and colorectal cancer incidence, agrees with Goodwin that therapies to reduce high insulin levels in cancer patients could dramatically reduce cancer-related deaths. “In postmenopausal women, where obesity is associated with a bad [breast cancer] outcome, it’s a very reasonable hypothesis that the bad outcome is because obesity is associated with high insulin,” he said. Two other large studies, using data from Canadian and British diabetes registries, have shown that people taking metformin, and thereby lowering their insulin levels, had unexpectedly lower overall cancer rates than patients taking diabetes medications such as sulfonylureas. These drugs work by raising insulin levels to force blood glucose levels down. “Previously the endocrinologists who used metformin to treat diabetes called it an insulinsensitizing agent because when type II diabetic patients were given metformin, their insulin levels fell. So the endocrinologists thought the drug was making the insulin work better,” said Pollak. But if metformin actually worked by making cells more sensitive to insulin, he said, it would probably increase tumor growth because insulin stimulates breast cancer cell growth. Pollak found that the opposite was true. When he studied the effect of metformin in both estrogen receptor – positive and estrogen receptor – negative breast cancer cells in culture, the drug reduced breast cancer cell growth.

Doctors Seek To Prevent Breast Cancer Recurrence by Lowering Insulin Levels